Mark R. Looney is a pulmonary and critical care physician at the University of California, San Francisco with a well-defined interest in acute lung injury and its basic mechanisms. Dr. Looney proposes in this application to develop three different in vivo mouse models of transfusion-related acute lung injury (TRALI), which is the leading cause of transfusion-related mortality in humans. The pathogenesis of TRALI is poorly understood and suffers from the lack of a clinically relevant in vivo animal model. Dr. Looney proposes to develop mouse models of TRALI by transfusing (1) monoclonal antibodies to mice with corresponding MHC I and II antigens, (2) polyclonal antibodies from alloimmunized mice to mismatched strains, and (3) older blood products with neutrophil priming activity to genetically identical mice. Also, he will use clinically relevant priming mechanisms (LPS, positive pressure ventilation) to potentially augment the response to the mouse models of TRALI. The versatility of three mouse models, and also the potential combination of individual models, will allow dissection of the pathogenic mechanisms responsible for acute lung injury. Dr. Looney postulates that the neutrophil will be a key cellular mediator of mouse TRALI and accordingly he will test the role of neutrophil and endothelial adhesion molecules, immune complex receptors, and activated complement receptors using gene knockout mice and cell depletion/reconstitution experiments. He also hypothesizes that the alveolar macrophage will play a role in mouse TRALI and will test this hypothesis with alveolar macrophage depletion and reconstitution experiments. Finally, the potential contribution of tissue mast cells will be tested by using mast cell deficient mice in selected models of experimental TRALI. By developing a relevant animal model of TRALI and carefully determining its pathogenic mechanisms, he will shed new light on this serious compliction of transfusion therapy. Dr. Looney has assembled an expert scientific advisory committee who will oversee his research and help implement an educational plan that will enrich his technical and intellectual development. The Cardiovascular Research Institute and the University of California, San Francisco are committed to developing the academic career of Dr. Looney, and at the end of the grant period, Dr. Looney will be well equipped to embark on a successful career as an independent investigator in the field of acute lung injury.